1. Field of the Invention
The present application relates to a process for the synthesis of polypeptides comprising the following amino acid units in the structure, namely, L-alanine, L-glutamic acid, L-lysine, and L-tyrosine. Glatiramer acetate, also known as copolymer-1, is a representative polypeptide of the present invention
2. Description of the Related Art
Glatiramer acetate is a mixture of polypeptides which has been approved for the treatment of multiple sclerosis. It is a mixture of acetate salts of chemically synthetic polypeptides, containing four naturally occurring amino acids: L-alanine, L-glutamic acid, L-lysine, and L-tyrosine typically with an average molar ratio of 0.392-0.462, 0.129-0.159, 0.300-0.374, and 0.086-01000, respectively. The average molecular weight of glatiramer acetate is 4,700-11,000 daltons.
Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is: (Glu, Ala, Lys, Tyr)x.xCH3COOH. Its CAS number is 147245-9-2-9.
Processes for preparing polypeptides of this type, including glatiramer acetate, have been described in U.S. Pat. Nos. 3,849,550 and 5,800,808; U.S. Patent Publication Nos. 2006/0172942; 2006/0154862; and 2007/0141663. The entire content of these patents and patent publications is incorporated herein as reference. The process for the preparation of the polypeptides of this type is based on the copolymerization of N-carboxyanhydride of tyrosine, N-carboxyanhydride of L-alanine, N-carboxyanhydride of protected L-glutamic acid and N-carboxyanhydride of protected L-lysine to form a protected copolymer. The deblocking of the protected L-glutamic acid is effected by acidolysis or hydrogenolysis (first deprotection) and is followed by the removal of the protecting group from L-lysine by base cleavage (second deprotection).
Typically, L-lysine is protected by a trifluoroacetyl group, and a nitrogen base with weak basicity, such as piperidine, is used to remove the protecting group of the L-Lysine. The nitrogen base usually has a concentration of more than 1 M in an amount of more than 35 molar equivalents of the L-lysine. Such a method is neither economic nor environmental.
Therefore, improvement of production of a polypeptide, such as glatiramer acetate, is desirable.